Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection.
BACKGROUND
Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences.


METHODS
To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5-12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or alphaPD1 ligand were studied.


RESULTS
Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus, CD4+ and CD8+ T cells, and activated microglia in perivascular areas and brain parenchyma. Genetically resistant, chronically infected mice had substantially less inflammation.


CONCLUSIONS
In outbred mice, chronic, adult acquired T. gondii infection causes neurologic and behavioral abnormalities secondary to inflammation and loss of brain parenchyma. Perivascular inflammation is prominent particularly contiguous to the aqueduct of Sylvius and hippocampus. Even resistant mice have perivascular inflammation. This mouse model of chronic T. gondii infection raises questions of whether persistence of this parasite in brain can cause inflammation or neurodegeneration in genetically susceptible hosts.
Hermes
Gretchen
G
Department of Ophthalmology, University of Chicago, Chicago, IL, USA. hermespin@aol.com
Ajioka
James W
JW
Kelly
Krystyna A
KA
Mui
Ernest
E
Roberts
Fiona
F
Kasza
Kristen
K
Mayr
Thomas
T
Kirisits
Michael J
MJ
Wollmann
Robert
R
Ferguson
David J P
DJ
Roberts
Craig W
CW
Hwang
Jong-Hee
JH
Trendler
Toria
T
Kennan
Richard P
RP
Suzuki
Yasuhiro
Y
Reardon
Catherine
C
Hickey
William F
WF
Chen
Lieping
L
McLeod
Rima
R
D000367:Age Factors; D000818:Animals; D001284:Atrophy / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000469:parasitology* / Q000473:pathology / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004660:Encephalitis / Q000469:parasitology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D020547:Lateral Ventricles / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000469:parasitology; D009410:Nerve Degeneration / Q000469:parasitology* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000469:parasitology* / Q000473:pathology; D014122:Toxoplasma / Q000166:cytology / Q000502:physiology; D016781:Toxoplasmosis, Cerebral / Q000473:pathology / Q000503:physiopathology*
D015415:Biomarkers; D009419:Nerve Tissue Proteins